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Transcript — Programme 116: Neuropathic Pain 2 of 2: Latest research

Half a cen­tu­ry worth of research exists on neu­ro­path­ic pain but what are the lat­est developments?

To lis­ten to this pro­gramme, please click here.

This edi­tion of Air­ing Pain is facil­i­tat­ed by the neu­ro­path­ic pain spe­cial inter­est group (NeuP­SIG) of the Inter­na­tion­al Asso­ci­a­tion for the Study of Pain (IASP).

With the pre­vi­ous edi­tion of Air­ing Pain focus­ing on the ‘psy­cho’ and ‘social’ of the bio-psy­cho-social mod­el, this pro­gramme tack­les the ‘bio’ component.

In this sec­ond instal­ment in a mini-series on neu­ro­path­ic pain, Paul Evans delves into the lat­est sci­en­tif­ic devel­op­ments on the con­di­tion and the ways in which the gap between research and treat­ments could be bridged.

Fol­low­ing on from Air­ing Pain 115, which con­cen­trat­ed on tar­get­ed Pain Man­age­ment Pro­grammes, this edi­tion dis­cuss­es the ‘bio’ ele­ment on deal­ing with neu­ro­path­ic pain. Speak­ing to Pro­fes­sor Srini­vasa Raja, Paul dis­cuss­es what exact­ly is going on in the brain with neu­ro­path­ic pain. Pro­fes­sor Raja pro­vides a valu­able expla­na­tion of the sci­ence behind the condition.

Patrick M. Dougher­ty, Pro­fes­sor at the Depart­ment of Pain Med­i­cine at The Uni­ver­si­ty of Texas MD Ander­son Can­cer Cen­tre then shares with Paul the lat­est advances in neu­ro­path­ic pain research. He exam­ines the link between can­cer treat­ments and the con­di­tion as well as the poten­tial for treat­ments such as immunother­a­py to com­bat neu­ro­path­ic pain in the future.

Issues cov­ered in this pro­gramme include: Neu­ro­path­ic pain, the bio-psy­choso­cial mod­el, allo­dy­nia, nerve injury, post-her­pet­ic neu­ral­gia, pain after shin­gles, pain after ampu­ta­tion, dif­fer­ences between men and women, chemother­a­py-relat­ed pain, can­cer, mul­ti­dis­ci­pli­nary pain teams, and per­son­alised pain man­age­ment ther­a­pies. 

Paul Evans: This is Air­ing Pain, a pro­gramme brought to you by Pain Con­cern, the UK char­i­ty pro­vid­ing infor­ma­tion and sup­port for those of us liv­ing with pain, and for health­care pro­fes­sion­als. I’m Paul Evans, and this edi­tion of Air­ing Pain has been sup­port­ed by the Inter­na­tion­al Asso­ci­a­tion for the Study of Pain.

Patrick Dougher­ty: The idea that you could use immunother­a­py for chron­ic neu­ro­path­ic pain – that’s a com­plete­ly new vista. This sort of research has only come up now over, like, the last three or four years. So this is a whole new vista.

Paul Evans: This is the sec­ond of two edi­tions of Air­ing Pain about neu­ro­path­ic pain, a con­di­tion caused by nerve dis­ease or nerve dam­age. The biopsy­choso­cial mod­el for man­ag­ing chron­ic pain recog­nis­es that the bio­log­i­cal, psy­cho­log­i­cal, and socio-envi­ron­men­tal fac­tors all feed into each oth­er and affect the pain. And that’s why mul­ti-dis­ci­pline pain teams made up of psy­chol­o­gists, phys­io­ther­a­pists, occu­pa­tion­al ther­a­pists, physi­cians and oth­er dis­ci­plines can be so effec­tive in help­ing peo­ple live with their pain.

In the pre­vi­ous edi­tion, we looked at how the psy­cho­log­i­cal and social ele­ments of peo­ple’s neu­ro­path­ic pain are addressed at the Nation­al Hos­pi­tal for Neu­rol­o­gy and Neu­ro­surgery Pain Man­age­ment Cen­tre in Lon­don, and I rec­om­mend you lis­ten to that. In this edi­tion, I want to look at the bio­log­i­cal com­po­nent of the biopsy­choso­cial trin­i­ty, and in par­tic­u­lar, to the progress or oth­er­wise, that’s been made into the under­stand­ing of neu­ro­path­ic pain, and what devel­op­ments and treat­ments might be just around the corner.

In May of this year, that’s 2019, the Inter­na­tion­al Asso­ci­a­tion for the Study of Pain brought togeth­er the world’s lead­ing experts on neu­ro­path­ic pain in Lon­don to share expe­ri­ence and knowl­edge. One of those is Pro­fes­sor Srini­vasa Raja of Johns Hop­kins School of Med­i­cine, Bal­ti­more, in the Unit­ed States. He’s inter­na­tion­al­ly recog­nised for his research into neu­ro­path­ic pain.

Srini­vasa Raja: One of the ear­li­er things that we were see­ing is that in patients who had nerve injuries, they had chron­ic pain, they would have pain long after their, quote-unquote, tis­sue injury healed. And they would come up with this sen­sa­tion, where they would say, you know: ‘Just touch­ing that area, or even rub­bing of things both­ered me.’ This phe­nom­e­non is called allo­dy­nia, or pain to sen­sa­tions that are nor­mal­ly not painful. So we were won­der­ing, you know, what could be caus­ing this, you know, is it because of change in how the nor­mal pain sig­nalling nerves or path­ways change? Or is it some­thing else?

So we brought some of these patients, and a sim­ple exper­i­ment we did was we applied a tourni­quet around their arms. So, after the tourni­quet, the sequence of loss of sen­sa­tions in nerves of dif­fer­ent sizes are vari­able. So the touch fibres are often lost first, and then the pain fibres. So as soon as these touch fibres were lost, you know, these patients lost the sen­sa­tion of this hyper­sen­si­tiv­i­ty, which told us that what’s hap­pened is, there were changes occur­ring at the lev­el of the cen­tral ner­vous sys­tem, such that this touch sen­sa­tion – which in the spinal cord at high­er cen­tres, has a com­mon ter­mi­na­tion with where the pain fibres go – there were changes in the lev­el of the spinal cord result­ing in a phe­nom­e­non called cen­tral sen­si­ti­sa­tion. That is, it’s almost like the ampli­fi­er or the vol­ume has been increased at the lev­el of the cen­tral ner­vous sys­tem, such that now even kind of acti­vat­ing these fibres, which on nor­mal indi­vid­u­als we would call as touch, now those indi­vid­u­als feel that as pain. So, this is one of the clin­i­cal aspects of under­stand­ing that injury to nerves changes how the cen­tral ner­vous sys­tem now per­ceives dif­fer­ent sen­sa­tions. And this also led to a lot of inves­ti­ga­tion by numer­ous inves­ti­ga­tors, look­ing specif­i­cal­ly at the lev­el of the spinal cord and even the brain, [at] what we now call the neu­ro­plas­tic­i­ty [of the brain], or how these sig­nalling mech­a­nisms change. And now we know the mol­e­c­u­lar biol­o­gy, we know a lot about it. And this has led also to pos­si­bly iden­ti­fy­ing tar­gets for treat­ing patients with this type of presentation.

Paul Evans: Let me go back a lit­tle bit to see if I under­stand this: a tourni­quet on my arm, and I will lose touch sen­sa­tion. Lots of us will have expe­ri­enced that, [for exam­ple] when we say: ‘oh my foot has gone to sleep’. At what point do you stop the pain signal?

Srini­vasa Raja: These patients, when they lost the sen­sa­tion of touch, could still feel a pin­prick, so their pain was still intact. But what they lost also was that hyper­sen­si­tiv­i­ty phe­nom­e­non where their touch result­ed in the sen­sa­tion of pain. And this is some­thing we com­mon­ly see, par­tic­u­lar­ly with patients with post-her­pet­ic neu­ral­gia or pain after shin­gles. You know, the com­mon site for shin­gles is often the chest wall. And women are much more prone – two-to-one, almost – [to expe­ri­ence this] than men. And the com­mon com­plaint that they’ll present to us is that [they] can’t wear a bra, you know, clothes are very uncom­fort­able. That rub­bing of the clothes on that skin is very uncomfortable.

Paul Evans: Explain to me now – we’ve gone through the putting the tourni­quet on and los­ing touch. What is going on in the brain with neu­ro­path­ic pain?

Srini­vasa Raja: This is a chal­leng­ing ques­tion, because we’re talk­ing about half the pain research com­mu­ni­ty, work­ing for almost half a cen­tu­ry try­ing to under­stand this. The good news is that we have made enor­mous progress in under­stand­ing the sci­ence, the mol­e­c­u­lar biol­o­gy, the neu­ro-phys­i­ol­o­gy or the changes in the ner­vous sys­tem. The unfor­tu­nate sad news is, it has­n’t been trans­lat­ed into new treat­ments for patients with neu­ro­path­ic pain. So there’s a big gap between the advances in research ver­sus what we call trans­lat­ing that into new treat­ments for patients. A sig­nif­i­cant new area of research is to try to under­stand why this gap [exists] and what may be caus­ing it. But to go back to answer­ing your ques­tion, what we have under­stood is that changes occur at every lev­el of the pain sig­nalling path­way. In cer­tain cas­es, this occurs at the lev­el of the periph­ery at the site of injury itself. Again, I’ll come back to the ampu­ta­tion exam­ple, where a nerve is often cut at the time of the ampu­ta­tion. And these cut nerves form what’s called a neu­ro­ma, which is a nerve try­ing to grow back to its orig­i­nal site. And these neu­ro­mas are very sen­si­tive, they are active, and they fire spon­ta­neous­ly, almost like seizure activ­i­ty of a periph­er­al nerve. And these sig­nals, [which are] con­stant­ly going from the periph­ery to the ner­vous sys­tem, are send­ing sig­nals to the brain say­ing [that] there is a prob­lem some­where in the periph­ery. So the first thing – and this phe­nom­e­na is called periph­er­al sen­si­ti­sa­tion, or changes in the periph­er­al ner­vous sys­tem. These, kind of, ongo­ing sig­nals in turn cause changes at mul­ti­ple lev­els in the cen­tral ner­vous sys­tem, at the lev­el of the spinal cord, the lev­el of the thal­a­mus in the brain and the cor­ti­cal lev­els, where this con­stant bar­rage of sig­nals changes how the cen­tral ner­vous sys­tem per­ceives the sig­nals. And it’s altered in a num­ber of ways, which glob­al­ly is called a cen­tral sen­si­ti­sa­tion. So this com­bi­na­tion of periph­er­al and cen­tral sen­si­ti­sa­tion in var­i­ous degrees can occur at dif­fer­ent brain states.

Paul Evans: So with an ampu­ta­tion, those nerves [which are] fir­ing off at the ampu­ta­tion, [are] look­ing for where they were, pre­sum­ably, and [are] maybe over­load­ing cir­cuits in the brain?

Srini­vasa Raja: You said that bet­ter than I explained. It is over­load­ing the sys­tem in some ways, result­ing in changes. Some of these changes seem to be more per­sis­tent than oth­ers. So, the strug­gle has been to see how we can revert this process, how we can reverse these changes occur­ring at the lev­el of the cen­tral ner­vous sys­tem, and that’s been a sig­nif­i­cant area for research.

Paul Evans: That’s Pro­fes­sor Srini­vasa Raja of Johns Hop­kins School of Med­i­cine in the Unit­ed States. Pro­fes­sor Patrick Dougher­ty is pro­fes­sor of pain research at the MD Ander­son Can­cer Insti­tute in Hous­ton in the Unit­ed States.

Patrick Dougher­ty: I’ve been inter­est­ed in neu­ro­path­ic pain, basi­cal­ly, ever since I was a post­doc or grad­u­ate stu­dent. And I was real­ly very inter­est­ed in how acti­va­tion of the immune sys­tem impacts us in such a dra­mat­ic fash­ion. So imag­ine the last time you were real­ly sick, how just godaw­ful you felt, and that biol­o­gy to me was extreme­ly fas­ci­nat­ing. Well, that car­ries straight over then into what hap­pens to the ner­vous sys­tem fol­low­ing periph­er­al injury. And so, ulti­mate­ly, that leads to what we know now is neu­ro­path­ic pain. Any type of injury that either leads to some sort of a chron­ic mal­adap­tive response in the ner­vous sys­tem, or direct injury to the ner­vous sys­tem that then leads to mal­adap­tive respons­es, result­ing in pain. Any of those would fit the cat­e­go­ry of what we call now neu­ro­path­ic pain. And so, ini­tial­ly, our work was focused on try­ing to tie [in] specif­i­cal­ly what we call psy­chophysics. Psy­chophysics means what peo­ple report when you apply ener­gy to skin. And we want to mod­el how human psy­chophysics is reflect­ed in the activ­i­ty of spe­cif­ic neu­rons with­in the cen­tral ner­vous sys­tem. And that was very suc­cess­ful, then led to an appoint­ment at Johns Hop­kins Uni­ver­si­ty, where I became inter­est­ed there in changes in neu­rons in the brain relat­ed then to neu­ro­path­ic pain.

That group of patients, now imag­ine the type of patient you’re look­ing at, they have neu­ro­path­ic pain that has been inad­e­quate­ly treat­ed to the point where they’re will­ing now to have a hole drilled in the top of their head, and put instru­men­ta­tion inside their brain to try to treat this pain. This is how far down the road they’ve suf­fered, basi­cal­ly, and what they’re now will­ing to try. And [when] I’m look­ing at that I’m think­ing, you know, these folks are so com­pli­cat­ed, we’re nev­er going to be able to fig­ure out mech­a­nisms in this con­di­tion. That then led me to think [about] neu­ro­path­ic pain, [in which] we know the patient starts off basi­cal­ly nor­mal, as far as pain goes, and then we cause neu­ro­path­ic pain. And that’s those folks that are get­ting can­cer treat­ments. Those peo­ple are basi­cal­ly neu­ro­log­i­cal­ly fine. They had can­cer, obvi­ous­ly, but they don’t have neu­ro­path­ic pain. We know exact­ly what the insult is, it’s the can­cer treat­ment. So the thought was, we could basi­cal­ly fol­low those peo­ple from before they get treat­ment, all the way to the end, [and then] we’ll be able to pro­file a whole nat­ur­al his­to­ry of neu­ro­path­ic pain. Then we can start to come back to oth­er folks that have neu­ro­path­ic pain, we can stage them in and apply ratio­nal ther­a­pies. That was the idea.

Paul Evans: So you’re going down a known route, [which is] peo­ple with can­cer, who’ve had treat­ment for their can­cer. Some get neu­ro­path­ic pain and some don’t. And you’re back­track­ing, then, for peo­ple who get neu­ro­path­ic pain, and you don’t know where it started.

Patrick Dougher­ty: That’s basi­cal­ly the idea. It does­n’t real­ly work out all that well. Because even can­cer treat­ment-relat­ed neu­ro­path­ic pain becomes very het­ero­ge­neous very quick­ly. In oth­er words, there’s a lot of branch points in the road. And so again, to try to back up to any­body becomes com­pli­cat­ed, but in any case, we can gain a lot of insights to the under­ly­ing mech­a­nisms. And there’s been a par­tic­u­lar advance­ment here late­ly, that is real­ly excit­ing to us. And that is, we found that you have a group of neu­rons that inner­vate your skin, those are called pri­ma­ry effer­ent neu­rons. And those pri­ma­ry effer­ent neu­rons have cell bod­ies that basi­cal­ly are what give them sus­te­nance, and meta­bol­ic sup­port, and those are called dor­sal root gan­glion neu­rons. So the dor­sal gan­glion neu­rons are those that send their axons out to every tis­sue in your body.

What we dis­cov­ered is that in basi­cal­ly every mod­el of neu­ro­path­ic pain now – and so this is where the road seems to con­verge – [in] every mod­el of neu­ro­path­ic pain that we’ve looked at so far, these dor­sal root gan­glion neu­rons become spon­ta­neous­ly active. They should­n’t be spon­ta­neous­ly active, par­tic­u­lar­ly if they’re a pain fibre. Pain fibres should be qui­et, unless you’re hav­ing pain. To find out that if we give ani­mals chemother­a­py drugs, and we go in and delib­er­ate­ly injure nerves to try to pro­duce a neu­ro­path­ic con­di­tion, these dor­sal root gan­glion neu­rons become spon­ta­neous­ly active in ani­mal mod­els. Lo and behold, in the course of just sim­ply talk­ing to peo­ple at MD Ander­son, it turns out that there’s a cohort of patients where their dor­sal root gan­glion neu­rons are going to be tak­en out in the course of try­ing to treat their can­cer, so they get can­cer into the spine, which is where near where the dor­sal root gan­glion lives, and some­times to treat that can­cer in the spine, those dor­sal root gan­glion neu­rons are tak­en out in order to get to the tumour.

What we found out is that if those gan­glion neu­rons in human beings come from a part of the body where that patient is expe­ri­enc­ing neu­ro­path­ic pain, lo and behold, they are also spon­ta­neous­ly active. So now we can take ani­mal mod­els of the spon­ta­neous activ­i­ty, and we can direct­ly line them up to the spon­ta­neous activ­i­ty that occurs in human neu­rons, and move back and forth, look­ing at those mech­a­nisms that are shared or dif­fer­ent between humans and the ani­mals. This is real­ly excit­ing, and a num­ber of dif­fer­ent labs now have con­firmed that find­ing, and this is prob­a­bly one of the biggest new move­ments in the field.

Paul Evans: Let me see if I can under­stand, ‘dor­sal root gan­glion’ – explain to me again what that is.

Patrick Dougher­ty: You may also hear it called, par­tic­u­lar­ly in the UK, ‘pos­te­ri­or root gan­glion’. The pos­te­ri­or root gan­glion and the dor­sal root gan­glion are what are called the cell bod­ies; the cen­tre of the neu­ron that leads to all of the periph­er­al end­ings that inner­vate your skin. So, when you move a hair on the back of your hand, there’s a neu­ron that’s back along your spinal cord that’s being acti­vat­ed by that. It has an axon that goes out and it wraps around the bot­tom of that hair cell, you move the hair, that caus­es that axon to dis­charge, that action poten­tial goes back past the gan­glion neu­ron and then into your spinal cord, [it] makes a synapse, [which is] a con­nec­tion to anoth­er neu­ron. That then even­tu­al­ly sends that infor­ma­tion to your brain and you realise: ‘Aha, a hair’s mov­ing on the back of my hand, some­thing’s hap­pened!’ And then every sen­sa­tion you can think of, for every part of your body, has a sep­a­rate dor­sal root gan­glion neu­ron that has an end­ing in that part of the skin, mus­cle, bone, ten­don, etc.

Paul Evans: So for can­cer patients hav­ing treat­ment, that path­way was broken?

Patrick Dougher­ty: Not bro­ken – let’s describe what hap­pens to can­cer patients when they get chemother­a­py drugs. There’s a num­ber of chemother­a­py drugs, not every chemother­a­py drug [results in neu­ro­path­ic pain], but there’s many chemother­a­py drugs. So for exam­ple, those used to treat breast can­cer, prostate can­cer, most every can­cer of a sol­id tis­sue and some blood can­cers, get sets of drugs that ulti­mate­ly result in what’s called neu­ro­path­ic pain. And what hap­pens for all of these class­es of drugs, and many peo­ple out there can attest to this. They prob­a­bly will be nod­ding their head: ‘Yes, that’s me.’

You get these drugs, first, it leads to numb­ness in their hands, that pro­gress­es to tin­gling. That’s prob­a­bly three quar­ters of patients [who] get those sen­sa­tions as they get those drugs. And that’s fine. Again, most­ly every­body’s going to get that, [and] most­ly every­body that gets bet­ter. But [for] some of those patients, that numb­ness and tin­gling pro­gress­es to the point where their hands and feet feel like they’re on fire. Unfor­tu­nate­ly, in about one-fifth of patients, that burn­ing sen­sa­tion, that numb­ness, that hor­ri­ble pins and nee­dles feel­ing, per­sists long after the can­cer treatment’s over and now they would fall into the cat­e­go­ry of neu­ro­path­ic pain patient.

Paul Evans: So you fol­low that track with cer­tain patients hav­ing can­cer treat­ment, and you try and repli­cate that.

Patrick Dougher­ty: Right, we can give ani­mals chemother­a­py drugs, though, we have to change our mea­sure­ments a lit­tle bit, because obvi­ous­ly, the ani­mals can’t tell us that they have ongo­ing pain, but there’s dif­fer­ent behav­iour­al mea­sure­ments that we can put the ani­mal in. So for exam­ple, folks that have got­ten Tax­ol, often what they’ll tell you is that cold applied to their skin feels like it’s burn­ing. So you can give ani­mals Tax­ol, now put them in a lit­tle room, and you [make] part of the floor cold, and part of the floor [not cold], and what you’ll see is that the ani­mal won’t go over to the cold floor, it’ll stay over on the warm floor. But since again, [with] the behav­iour in the ani­mal, you’re always kind of guess­ing what that means. I’m always real­ly inter­est­ed in what we can objec­tive­ly mea­sure. And that’s why I say when we find that you get this ectopic spon­ta­neous activ­i­ty of the neu­rons that oth­er­wise should be qui­et. And you can see the same thing in peo­ple. That’s what I like to zero in on, we don’t have to guess what it means: either that cell is dis­charg­ing, it’s on, or it’s off. And then [with] peo­ple it’s either on or it’s off. And if we can fig­ure out how to take the cells that are on and make them shut off, then the idea is that that’s what’s going to relieve their symptoms.

Paul Evans: Go on, then, can you?

Patrick Dougher­ty: We are mak­ing a lot of inter­est­ing progress. So the phys­i­ol­o­gy gets to be real­ly com­pli­cat­ed real­ly fast. But there are a num­ber of poten­tial ther­a­peu­tic avenues that have been uncov­ered, that now we need to fig­ure out how can we oper­a­tional­ize. There’s ques­tions that have arisen that are very sur­pris­ing. So there’s a paper we pub­lished a month ago or so, where what we did in that paper – we had these human neu­rons. In my lab, we did the phys­i­ol­o­gy, and we deter­mined which of these gan­glion neu­rons that we had were in sam­ples asso­ci­at­ed with pain and with the spon­ta­neous activ­i­ty. The human gan­glion is big enough that we could divide it, and we can share part of that tis­sue with anoth­er lab­o­ra­to­ry in Dal­las, head­ed by a fel­low named Ted Price. Ted’s group broke those gan­glion neu­rons apart and start­ed look­ing at what we call their tran­scrip­tome. And the tran­scrip­tome is basi­cal­ly an out­put from their DNA. In oth­er words, what part of the DNA were those cells acti­vat­ing, that we think would be relat­ed to the gen­er­a­tion of the spon­ta­neous activ­i­ty. So we want­ed to know, then what sorts of pro­teins are being made that either weren’t made before, or that used to be made that aren’t any longer being made. Again, the idea that we can reveal poten­tial new ther­a­peu­tic tar­gets. And so, Ted did all this analy­sis. And what we did ini­tial­ly is we took all the gan­glion neu­rons that we had from der­matomes, or seg­ments of the body where patients had pain. And we com­pared the genet­ic infor­ma­tion com­ing from all of the neu­rons from der­matomes with­out pain. And we run the analy­sis, and lo and behold, we got almost noth­ing, we could­n’t believe that – that could­n’t pos­si­bly be the right answer. Final­ly, we decid­ed, you know, let’s just go ahead and we’ll pull all the women out, we’ll just sep­a­rate men from women.

Then what we did was, we ran all of the neu­rons from men, seg­ment pain; men seg­ment no pain, and voila, we got a huge num­ber of results. What that tells us is that men and women are actu­al­ly chang­ing dif­fer­ent gene sig­nals dif­fer­en­tial­ly with pain. So in oth­er words, men are from Mars, and women are from Venus. In fact, we have quite dis­tinct mech­a­nisms by which our bod­ies, in this case, our neu­rons, respond to this insult – the tox­ic chemother­a­py drug that then results in dif­fer­ent ways of express­ing pain. Now, what [does] that ther­a­peu­ti­cal­ly mean? Well, that means that if you give a giv­en drug to a man, that might work, [but] that same drug giv­en to a woman may not. And then if you fur­ther fol­low the log­ic to that, even for a giv­en man, there’s going to be vari­abil­i­ty with­in the male cohort. So even a drug that works in man num­ber one may not work in man num­ber two. It’s lead­ing to the prospect that what we’re real­ly going to need to do is come up with sets of what we call bio­mark­ers, and these gene sig­nals are a type of bio­mark­er, there’s oth­ers. But we’re going to prob­a­bly need to get sets of bio­mark­ers for each per­son, and then there­by come up with spe­cif­ic ther­a­peu­tics for each indi­vid­ual person.

Paul Evans: Wow, how or when will that impact on peo­ple with neu­ro­path­ic pain?

Patrick Dougher­ty: That’s a huge­ly con­vo­lut­ed ques­tion, I think, you know. So num­ber one, there are num­bers of com­pounds that are out there that are avail­able now. Most pain clin­ics have a set of drugs, and they try dif­fer­ent sets for dif­fer­ent patients. Some folks respond to one type of agent, oth­ers respond to anoth­er. So the pain clin­ics already under­stand that you have to tai­lor each pain ther­a­py specif­i­cal­ly to each patient. So that con­cept is already in place. What our research is show­ing is that we need a broad­er palette of ther­a­peu­tics to address giv­en folks, my lab is not alone in this approach. So there are a num­ber of labs here in the UK that also are doing very sim­i­lar work to us, in that they’ve got the same tis­sues, they’re also doing these same kinds of analy­ses. And one of the oth­er things that we’ve dis­cov­ered in these gan­glion neu­rons that’s real­ly impor­tant is that part of what caus­es these neu­rons to become active, is that when the gan­glion becomes dam­aged, becomes inflamed, you get immune cells that go in there – and this is kind of fun­ny, because it clos­es the loop on my whole career – that’s what it began with: how immune cells impact the brain.

It turns out that these gan­glion become infil­trat­ed by sets of immune cells, some are your angry uncle, and oth­ers are your sooth­ing grand­moth­er. And you can actu­al­ly train the grand­moth­er cells to go in and qui­et every­thing down. And so with that idea being that you have immune cells that actu­al­ly get into the gan­glion that can either make things worse or bet­ter with one poten­tial bio­mark­er, and there’s oth­er labs that are doing this, you could take a blood test, and from what’s in your blood – the immune cells that are in your blood – you may be able to get a pic­ture of what poten­tial­ly has gone into your gan­glion that’s either dri­ving that dis­ease or that we can manip­u­late to try to make that dis­ease go away. So the idea that you could use immunother­a­py for chron­ic neu­ro­path­ic pain, that’s a com­plete­ly new vista that again, has been revealed by these new stud­ies on gan­glia and what’s going on in those ganglia.

So this sort of research has only come up now over like the last three or four years. So this is a whole new vista and what we sim­ply need to do now is build up the sam­ple sizes, I would say, you know, opti­misti­cal­ly, as rapid­ly as biotech and the rest is advanced, let’s say five years, we can start actu­al­ly hav­ing some real insights of what may be real­ly good play­ers to fol­low. And then it will be up to the phar­ma out­fits and the new biotech out­fits to oper­a­tional­ize those tar­gets and come up with ther­a­peu­tics. My side of the ledger is what’s called tar­get iden­ti­fi­ca­tion. Once you get tar­gets that are well val­i­dat­ed, then you get into the legal­is­tic part of bring­ing a drug to mar­ket. And so, I can’t tell you how long that might take based on which gov­ern­ment you’re work­ing with. If it’s in the US, it can be very slow, oth­er coun­tries move faster. So it’s hard to pre­dict once you get into the actu­al reg­u­la­to­ry process for each place, but I think as far as tar­get iden­ti­fi­ca­tion goes, I would say with­in five years, we are going to have a very good idea of some promis­ing new tar­gets. I would say today, you know, our data says that a num­ber of those that we could fol­low, but we need to val­i­date the tar­gets that we’ve iden­ti­fied. Oth­er labs are iden­ti­fy­ing oth­er tar­gets, those should be mature enough, with­in five years, that you could start to oper­a­tional­ize those into ther­a­peu­tics, and then you get into the ther­a­peu­tic reg­u­la­to­ry process, so that I can’t give you a han­dle on.

Paul Evans: That sounds very excit­ing, very pos­i­tive. I guess it should­n’t real­ly come as a sur­prise that the same drug will work dif­fer­ent­ly on dif­fer­ent indi­vid­u­als. When we open our tablets, we see the list of the side effects, which could be diar­rhoea, it could be con­sti­pa­tion, it could be one of a hun­dred things, you know. Per­son­al­is­ing design­er drugs sounds real­ly exciting.

Patrick Dougher­ty: Yeah, and it goes beyond just drugs, right? Peo­ple need to be aware that pain, par­tic­u­lar­ly a chron­ic pain con­di­tion, is not prob­a­bly going to be treat­ed by any mag­ic-bul­let drug. I mean, you’re going to need to go into what­ev­er you can pos­si­bly do, that might work for you. Is that walk­ing? Is it swim­ming? Is it yoga? Is it med­i­ta­tion? You know, there’s a whole num­ber of dif­fer­ent – both med­ical or drug – ther­a­pies and then non-med­ical therapies.

So MD Ander­son, that is one of the pain treat­ment cen­tres – what’s called a mul­ti­dis­ci­pli­nary pain cen­tre – where basi­cal­ly what­ev­er works for a giv­en patient is what you’re going to try. And it’s prob­a­bly not going to be one thing, there’s prob­a­bly not one mag­ic bul­let. Num­ber one, the patient has to decide they want to get bet­ter. It’s all about patient buy in: if you give up, the chances of being fixed are small. So you have to be focused, that you are going to get bet­ter, this is a dis­ease you’re going to over­come. Then you find the com­bi­na­tion of med­ica­tions that work, the com­bi­na­tion of exer­cise, the com­bi­na­tion of nutri­tion, etc., that works for you to get you back, so that you’re in the game and you’re func­tion­al again.

Paul Evans: That’s Pro­fes­sor Patrick Dougher­ty, of MD Ander­son Can­cer Insti­tute in Hous­ton. And I was speak­ing to him and Pro­fes­sor Srini­vasa Raja, at the Inter­na­tion­al Asso­ci­a­tion for the Study of Pain Neu­ro­path­ic Pain Spe­cial Inter­est Group con­fer­ence ear­li­er this year, in Lon­don. I will just remind you that whilst we in Pain Con­cern believe the infor­ma­tion and opin­ions on Air­ing Pain are accu­rate and sound, based on the best judg­ments avail­able, you should always con­sult your health pro­fes­sion­al on any mat­ter relat­ing to your health and well­be­ing. He or she is the only per­son who knows you and your cir­cum­stances and, there­fore, the appro­pri­ate action to take on your behalf.

Well, in this edi­tion of Air­ing Pain, we’ve been focus­ing on the ‘bio’: the bio­log­i­cal ele­ments of the biopsy­choso­cial mod­el for chron­ic pain. And please do lis­ten to the pre­vi­ous edi­tion of Air­ing Pain to learn more about these psy­cho­log­i­cal and social elements.

Patrick Dougher­ty: They’re cru­cial. They’re absolute­ly cru­cial. If a per­son has chron­ic pain, and they become social­ly with­drawn, iso­lat­ed, that quick­ly leads to depres­sion, and an ero­sion of the spir­it. And that per­son then is going to suf­fer even more. You have to get your­self back engaged into social envi­ron­ments, work­ing as hard as you can to get your­self back to a nor­mal lev­el of activ­i­ty. Mean­while, we’ll be in the lab try­ing to come up with as many mag­ic bul­lets as we can come up with. But I would be very sur­prised if we find any­thing that I say is the gold­en tick­et, so to speak. It’s going to be a com­bi­na­tion of things. Every­one’s going to have to sort out what specif­i­cal­ly is going on with them in con­cert with their med­ical providers. What we’re hop­ing to do is come up with the tools and resources that, num­ber one, we can [use to] bet­ter ascer­tain for that par­tic­u­lar per­son what’s going on with them. And then, again, have the agents that can be then implemented.


  • Patrick M. Dougher­ty, Pro­fes­sor at the Depart­ment of Pain Med­i­cine, Divi­sion of Anaes­the­si­ol­o­gy and Crit­i­cal Care, The Uni­ver­si­ty of Texas MD Ander­son Can­cer Cen­tre, Houston.
  • Pro­fes­sor Srini­vasa Raja (John Hop­kins School of Med­i­cine, USA).

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